bims-ciryme 2023-10-15 papers

F1000Res. 2023 ;12 49

Circadian disruption does not alter tumorigenesis in a mouse model of lymphoma.

Rebecca M Mello, Marie Pariollaud, Katja A Lamia.

Background: Disruption of natural light cycles, as experienced by shift workers, is linked to enhanced cancer incidence. Several mouse models of cancer develop more severe disease when exposed to irregular light/dark cycles, supporting the connection between circadian disruption and increased cancer risk. Cryptochrome 2 (CRY2), a repressive component of the molecular circadian clock, facilitates turnover of the oncoprotein c-MYC, one mechanism that may link the molecular clock to tumorigenesis. In Eμ-MYC mice, which express transgenic c-MYC in B cells and develop aggressive lymphomas and leukemia, global Cry2 deletion reduces survival and enhances tumor formation. Lighting conditions that mimic the disruption experienced by shift workers dampen Cry2 transcripts in peripheral tissues of C57BL/6J mice. Although it is milder than homozygous deletion of Cry2, we hypothesized that reduced Cry2 rhythmicity could alter MYC protein accumulation and contribute to enhanced cancer risk caused by circadian disruption. We tested this hypothesis in MYC-driven lymphoma. Methods: We housed Eμ-MYC mice in light-tight boxes set to either control (continuous cycles of 12-hours of light followed by 12-hours of dark, LD12:12) or chronic jetlag (eight-hour light phase advances every two to three days, CJL) lighting conditions and assessed the impact of disrupted light cycles on survival and tumor formation in Eμ-MYC mice. Results: Environmental disruption of circadian rhythms did not alter tumor location, tumor growth, or survival in Eμ-MYC mice. Conclusions: Dampened rhythms of Cry2 following disruption of circadian light exposures is milder than deletion of Cry2. The lack of phenotype caused by altered circadian gene expression in contrast to enhanced tumorigenesis caused by homozygous deletion of Cry2 suggests that CRY2 dosage impacts this model. Importantly, these findings indicate that increased cancer risk associated with circadian disruption arises from one or more mechanisms that are not recapitulated here, and may be different in distinct tumor types.

Keywords: CRY2; c-MYC; chronic jetlag; circadian disruption; circadian rhythm; lymphoma

DOI: https://doi.org/10.12688/f1000research.125272.2

Sci Rep. 2023 Oct 09. 13(1): 16974

In vivo recording of the circadian calcium rhythm in Prokineticin 2 neurons of the suprachiasmatic nucleus.

Kaito Onodera, Yusuke Tsuno, Yuichi Hiraoka, Kohichi Tanaka, Takashi Maejima, Michihiro Mieda.

Prokineticin 2 (Prok2) is a small protein expressed in a subpopulation of neurons in the suprachiasmatic nucleus (SCN), the primary circadian pacemaker in mammals. Prok2 has been implicated as a candidate output molecule from the SCN to control multiple circadian rhythms. Genetic manipulation specific to Prok2-producing neurons would be a powerful approach to understanding their function. Here, we report the generation of Prok2-tTA knock-in mice expressing the tetracycline transactivator (tTA) specifically in Prok2 neurons and an application of these mice to in vivo recording of Ca2+ rhythms in these neurons. First, the specific and efficient expression of tTA in Prok2 neurons was verified by crossing the mice with EGFP reporter mice. Prok2-tTA mice were then used to express a fluorescent Ca2+ sensor protein to record the circadian Ca2+ rhythm in SCN Prok2 neurons in vivo. Ca2+ in these cells showed clear circadian rhythms in both light-dark and constant dark conditions, with their peaks around midday. Notably, the hours of high Ca2+ nearly coincided with the rest period of the behavioral rhythm. These observations fit well with the predicted function of Prok2 neurons as a candidate output pathway of the SCN by suppressing locomotor activity during both daytime and subjective daytime.

DOI: https://doi.org/10.1038/s41598-023-44282-5

Proc Natl Acad Sci U S A. 2023 Oct 17. 120(42): e2301608120

Associations between light exposure and sleep timing and sleepiness while awake in a sample of UK adults in everyday life.

Altug Didikoglu, Navid Mohammadian, Sheena Johnson, Martie van Tongeren, Paul Wright, Alexander J Casson, Timothy M Brown, Robert J Lucas.

Experimental and interventional studies show that light can regulate sleep timing and sleepiness while awake by setting the phase of circadian rhythms and supporting alertness. The extent to which differences in light exposure explain variations in sleep and sleepiness within and between individuals in everyday life remains less clear. Here, we establish a method to address this deficit, incorporating an open-source wearable wrist-worn light logger (SpectraWear) and smartphone-based online data collection. We use it to simultaneously record longitudinal light exposure (in melanopic equivalent daylight illuminance), sleep timing, and subjective alertness over seven days in a convenience sample of 59 UK adults without externally imposed circadian challenge (e.g., shift work or jetlag). Participants reliably had strong daily rhythms in light exposure but frequently were exposed to less light during the daytime and more light in pre-bedtime and sleep episodes than recommended [T. M. Brown et al., PLoS Biol. 20, e3001571 (2022)]. Prior light exposure over several hours was associated with lower subjective sleepiness with, in particular, brighter light in the late sleep episode and after wake linked to reduced early morning sleepiness (sleep inertia). Higher pre-bedtime light exposure was associated with longer sleep onset latency. Early sleep timing was correlated with more reproducible and robust daily patterns of light exposure and higher daytime/lower night-time light exposure. Our study establishes a method for collecting longitudinal sleep and health/performance data in everyday life and provides evidence of associations between light exposure and important determinants of sleep health and performance.

Keywords: light; melanopic; sleep; sleepiness

DOI: https://doi.org/10.1073/pnas.2301608120

Nat Commun. 2023 Oct 11. 14(1): 6381

A clock-dependent brake for rhythmic arousal in the dorsomedial hypothalamus.

Qiang Liu, Benjamin J Bell, Dong Won Kim, Sang Soo Lee, Mehmet F Keles, Qili Liu, Ian D Blum, Annette A Wang, Elijah J Blank, Jiali Xiong, Joseph L Bedont, Anna J Chang, Habon Issa, Jeremiah Y Cohen, Seth Blackshaw, Mark N Wu.

Circadian clocks generate rhythms of arousal, but the underlying molecular and cellular mechanisms remain unclear. In Drosophila, the clock output molecule WIDE AWAKE (WAKE) labels rhythmic neural networks and cyclically regulates sleep and arousal. Here, we show, in a male mouse model, that mWAKE/ANKFN1 labels a subpopulation of dorsomedial hypothalamus (DMH) neurons involved in rhythmic arousal and acts in the DMH to reduce arousal at night. In vivo Ca2+ imaging reveals elevated DMHmWAKE activity during wakefulness and rapid eye movement (REM) sleep, while patch-clamp recordings show that DMHmWAKE neurons fire more frequently at night. Chemogenetic manipulations demonstrate that DMHmWAKE neurons are necessary and sufficient for arousal. Single-cell profiling coupled with optogenetic activation experiments suggest that GABAergic DMHmWAKE neurons promote arousal. Surprisingly, our data suggest that mWAKE acts as a clock-dependent brake on arousal during the night, when mice are normally active. mWAKE levels peak at night under clock control, and loss of mWAKE leads to hyperarousal and greater DMHmWAKE neuronal excitability specifically at night. These results suggest that the clock does not solely promote arousal during an animal's active period, but instead uses opposing processes to produce appropriate levels of arousal in a time-dependent manner.

DOI: https://doi.org/10.1038/s41467-023-41877-4